Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004352 (autism)
 32,579 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-1-Receptor Accessory Protein Like 1 (IL1RAPL1) gene mutations are associated to cognitive impairment ranging from non-syndromic X-linked mental retardation to autism. Functionally IL1RAPL1 belongs to a novel family of Toll/IL-1 Receptors, but its ligand is unknown. In a recent study, we have shown that IL1RAPL1 is present in dendritic spine where it interacts with PSD-95, a major scaffold protein of excitatory post-synaptic density. We demonstrated that IL1RAPL1 regulates the synaptic localization of PSD-95 by controlling JNK (c-Jun terminal Kinase) activity and PSD-95 phosphorylation. Loss of IL1RAPL1 in mouse not only led to a reduction of excitatory synapses but also to specific deficits in hippocampal long-term synaptic plasticity. Here we report that activation of JNK pathway in neurons by Interleukin-1 (IL-1) is mediated by IL1RAPL1. The interaction of IL1RAPL1 with PSD-95 discloses a novel pathophysiological mechanism underlying cognitive impairment associated with alterations of the JNK pathway in response to IL-1 and leading to the mislocalization of PSD-95, that subsequently result in abnormal synaptic organization and function.
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PMID:Neuronal JNK pathway activation by IL-1 is mediated through IL1RAPL1, a protein required for development of cognitive functions. 2071 5

It has been reported that neuroinflammation occurs in the central nervous system (CNS) in patients with neuropathic pain, Alzheimer's disease and autism spectrum disorder. The 18-kDa translocator protein TSPO is used as an imaging target in positron emission tomography to detect neuroinflammation, and its expression is correlated with microglial activation. However, the mechanism underlying the transcriptional regulation of Tspo induced by inflammation is not clear. Here, we revealed that lipopolysaccharide (LPS) -induced Tspo expression was activated by the AP-1 complex in a mouse microglial cell line, BV-2. Knockdown of c-Fos and c-Jun, the components of AP-1, reduced LPS-induced Tspo expression. Furthermore, the enrichment of Sp1 in the proximal promoter region of Tspo was increased in the presence of LPS. In addition, the binding of histone deacetylase 1 (HDAC1) to the enhancer region, which contains the AP-1 site, was decreased by LPS treatment, but there were no significant differences in HDAC1 binding to the proximal promoter region with or without LPS. These results indicated that HDAC1 is involved not in the proximal promoter region but in the enhancer region. Our study revealed that inflammatory signals induce the recruitment of AP-1 to the enhancer region and Sp1 to the proximal promoter region of the Tspo gene and that Sp1 may regulate the basal expression of Tspo.
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PMID:Lipopolysaccharide induces mouse translocator protein (18 kDa) expression via the AP-1 complex in the microglial cell line, BV-2. 3153 3

Aberrant migration of inhibitory interneurons can alter the formation of cortical circuitry and lead to severe neurologic disorders including epilepsy, autism, and schizophrenia. However, mechanisms involved in directing the migration of interneurons remain incompletely understood. Using a mouse model, we performed live-cell confocal microscopy to explore the mechanisms by which the c-Jun NH2-terminal kinase (JNK) pathway coordinates leading process branching and nucleokinesis, two cell biological processes that are essential for the guided migration of cortical interneurons. Pharmacological inhibition of JNK signaling disrupts the kinetics of leading process branching, rate and amplitude of nucleokinesis, and leads to the rearward mislocalization of the centrosome and primary cilium to the trailing process. Genetic loss of Jnk from interneurons also impairs leading process branching and nucleokinesis, suggesting that important mechanics of interneuron migration depend on the intrinsic activity of JNK. These findings highlight key roles for JNK signaling in leading process branching, nucleokinesis, and the trafficking of centrosomes and cilia during interneuron migration, and further implicates JNK signaling as an important mediator of cortical development.
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PMID:JNK Signaling Regulates Cellular Mechanics of Cortical Interneuron Migration. 3273 85